bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2022–08–14
thirty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. miR-196b-TLR7/8 signaling axis regulates innate immune signaling and myeloid maturation in DNMT3A-mutant AML.
  2. MOZ is critical for the development of MOZ/MLL-fusion-induced leukemia through regulation of Hoxa9/Meis1 expression.
  3. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine.
  4. Unified classification and risk-stratification in Acute Myeloid Leukemia.
  5. c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia.
  6. Potent preclinical activity of FLT3-directed chimeric antigen receptor T cell immunotherapy against FLT3-mutant acute myeloid leukemia and KMT2A-rearranged acute lymphoblastic leukemia.
  7. Comparison of scoring systems evaluating suitability for intensive chemotherapy in adults with acute myeloid leukemia-a Grand Ouest Against Leukemia (GOAL) study.
  8. Multiple gene knockdown strategies for investigating the properties of human leukemia stem cells and exploring new therapies.
  9. Activation of signaling pathways in models of t(6;9)-acute myeloid leukemia.
  10. Alternatively spliced CSF3R isoforms in SRSF2 P95H mutated myeloid neoplasms.
  11. An immunity and pyroptosis gene-pair signature predicts overall survival in acute myeloid leukemia.
  12. Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance.
  13. Sorafenib maintenance after hematopoietic stem cell transplantation improves outcome of FLT3-ITD-mutated acute myeloid leukemia.
  14. Distinguishing STAT3/STAT5B Mutated Large Granular Lymphocyte Leukemia from Myeloid Neoplasms by Genetic Profiling.
  15. Diverse mutational landscapes in human lymphocytes.
  16. Single-cell analysis of transcription factor regulatory networks reveals molecular basis for subtype-specific dysregulation in acute myeloid leukemia.
  17. Pharmacogenomic profiling of pediatric acute myeloid leukemia to identify therapeutic vulnerabilities and inform functional precision medicine.
  18. Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size.
  19. Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis.
  20. MYC sensitises cells to apoptosis by driving energetic demand.
  21. Gilteritinib as treatment for extra-medullary relapse of FLT3-ITD acute myeloid leukemia FLT3-ITD, after allogeneic haematopoietic stem cell transplantation.
  22. A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.
  23. The Impact of Clonal Hematopoiesis on Cardiovascular Disease in People Living with HIV.
  24. Pre-transplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines post-transplant clinical outcome.
  25. Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells.
  26. A distinct lipid metabolism signature of acute myeloid leukemia with prognostic value.
  27. The Anti-Leukemia Effect of Ascorbic Acid: From the Pro-Oxidant Potential to the Epigenetic Role in Acute Myeloid Leukemia.
  28. Blasts in context: the impact of the immune environment on acute myeloid leukemia prognosis and treatment.
  29. Discovery of compounds that reactivate p53 mutants in vitro and in vivo.
  30. Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease.
  31. Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.
  32. Single-cell diploid Hi-C reveals the role of spatial aggregations in complex rearrangements and KMT2A fusions in leukemia.
  33. Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300.
  34. Substitution mutational signatures in whole-genome-sequenced cancers in the UK population.
  35. Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance.
  36. Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells.
  1. Clin Cancer Res. 2022 Aug 09. pii: CCR-22-1598. [Epub ahead of print]
    miR-196b-TLR7/8 signaling axis regulates innate immune signaling and myeloid maturation in DNMT3A-mutant AML.
    Holly A Gamlen, Jennifer S Romer-Seibert, Michael E Lawler, Amanda M Versace, Melanie L Goetz, Yang Feng, Olga A Guryanova, Neil Palmisiano, Sara E Meyer.
       PURPOSE: DNMT3A mutations confer a poor prognosis in acute myeloid leukemia (AML), but the molecular mechanisms downstream of DNMT3A mutations in disease pathogenesis are not completely understood, limiting targeted therapeutic options. The role of microRNA in DNMT3A-mutant AML pathogenesis is understudied.
    EXPERIMENTAL DESIGN: DNA methylation and miRNA expression was evaluated in human AML patient samples and in Dnmt3a/Flt3-mutant AML mice. The treatment efficacy and molecular mechanisms of TLR7/8-directed therapies on DNMT3A-mutant AML were evaluated in vitro on human AML patient samples and in Dnmt3a/Flt3-mutant AML mice.
    RESULTS: miR-196b is hypomethylated and overexpressed in DNMT3A-mutant AML and is associated with poor patient outcome. miR-196b overexpression in DNMT3A-mutant AML is important to maintain an immature state and leukemic cell survival through repression of TLR signaling. The TLR7/8 agonist Resiquimod induces dendritic cell-like differentiation with co-stimulatory molecule expression in DNMT3A-mutant AML cells and provides a survival benefit to Dnmt3a/Flt3-mutant AML mice. The small molecule Bryostatin-1 augments Resiquimod-mediated AML growth inhibition and differentiation.
    CONCLUSIONS: DNMT3A loss-of-function mutations cause miRNA locus-specific hypomethylation and overexpression important for mutant DNMT3A-mediated pathogenesis and clinical outcomes. Specifically, the overexpression of miR-196b in DNMT3A-mutant AML creates a novel therapeutic vulnerability by controlling sensitivity to TLR7/8-directed therapies.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-1598
  2. Blood Adv. 2022 Aug 10. pii: bloodadvances.2020003490. [Epub ahead of print]
    MOZ is critical for the development of MOZ/MLL-fusion-induced leukemia through regulation of Hoxa9/Meis1 expression.
    Takuo Katsumoto, Yoko Ogawara, Kazutsune Yamagata, Yukiko Aikawa, Ryo Goitsuka, Takuro Nakamura, Issay Kitabayashi.
      MOnocytic leukemia Zinc finger protein (MOZ, MYST3, or KAT6A) is a MYST-type acetyltransferase involved in chromosomal translocation in acute myelogenous leukemia (AML) and myelodysplastic syndrome. MOZ is established as essential for hematopoiesis; however, the role of MOZ in AML has not been addressed. We propose that MOZ is critical for AML development induced by MLL-AF9, MLL-AF10, or MOZ-TIF2 fusions. Moz-deficient hematopoietic stem/progenitor cells (HSPCs) transduced with an MLL-AF10 fusion gene neither formed colonies in methylcellulose nor induced AML in mice, and Moz-deficient HSPCs bearing MLL-AF9 also generated significantly reduced colony and cell numbers. Moz-deficient HSPCs expressing MOZ-TIF2 could form colonies in vitro but could not induce AML in mice. By contrast, Moz was dispensable for colony formation by HOXA9-transduced cells and AML development caused by HOXA9 and MEIS1, suggesting a specific requirement for MOZ in AML induced by MOZ/MLL-fusions. Expression of the Hoxa9 and Meis1 genes was decreased in Moz-deficient MLL-fusion expressing cells, while expression of Meis1, but not Hoxa9, was reduced in Moz-deficient MOZ-TIF2 AML cells. AML development induced by MOZ-TIF2 was rescued by introducing Meis1 into Moz-deficient cells carrying MOZ-TIF2. Meis1 deletion impaired MOZ-TIF2¬-mediated AML development. MOZ-TIF2 and endogenous Moz binding and active histone modifications were also severely reduced at the Meis1 locus in Moz-deficient MOZ-TIF2 and MLL-AF9 AML cells. These results suggest that endogenous MOZ is critical for MOZ/MLL-fusion-induced AML development and maintains fusion binding and active chromatin signatures at target gene loci.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003490
  3. Blood. 2022 Aug 12. pii: blood.2022016293. [Epub ahead of print]
    Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine.
    Hartmut Döhner, Andrew H Wei, Gail J Roboz, Pau Montesinos, Felicitas R Thol, Farhad Ravandi, Hervé Dombret, Kimmo Porkka, Irwindeep Sandhu, Barry S Skikne, Wendy L See, Manuel Ugidos, Alberto Risueño, Esther T Chan, Anjan Thakurta, C L Beach, Daniel Lopes de Menezes.
      The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with AML in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplant. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days/28-day cycle. We evaluated relapse-free (RFS) and overall (OS) survival in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis, and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1mut, 66 (14.1%) had FLT3mut (-ITD and/or -TKDmut), and 30 (6.4%) had NPM1mut/FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (HR 0.63 [95%CI 0.41-0.98]) and 45% (0.55 [0.35-0.84]), respectively, vs placebo. Median OS was numerically improved with Oral-AZA among NPM1mut patients whether MRD- (48.6 months, vs 31.4 months with placebo) or MRD+ (46.1 vs 10.0 months) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR 0.63 [95%CI 0.35-1.12]) and 49% (0.51 [0.27-0.95]), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 vs 16.2 months, respectively, for FLT3mut/MRD- patients, and 24.0 vs 8.0 months for FLT3mut/MRD+ patients. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.
    DOI:  https://doi.org/10.1182/blood.2022016293
  4. Nat Commun. 2022 Aug 08. 13(1): 4622
    Unified classification and risk-stratification in Acute Myeloid Leukemia.
    Yanis Tazi, Juan E Arango-Ossa, Yangyu Zhou, Elsa Bernard, Ian Thomas, Amanda Gilkes, Sylvie Freeman, Yoann Pradat, Sean J Johnson, Robert Hills, Richard Dillon, Max F Levine, Daniel Leongamornlert, Adam Butler, Arnold Ganser, Lars Bullinger, Konstanze Döhner, Oliver Ottmann, Richard Adams, Hartmut Döhner, Peter J Campbell, Alan K Burnett, Michael Dennis, Nigel H Russell, Sean M Devlin, Brian J P Huntly, Elli Papaemmanuil.
      Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.
    DOI:  https://doi.org/10.1038/s41467-022-32103-8
  5. Apoptosis. 2022 Aug 09.
    c-Myc plays a critical role in the antileukemic activity of the Mcl-1-selective inhibitor AZD5991 in acute myeloid leukemia.
    Shuang Liu, Xinan Qiao, Shuangshuang Wu, Yuqinq Gai, Yongwei Su, Holly Edwards, Yue Wang, Hai Lin, Jeffrey W Taub, Guan Wang, Yubin Ge.
      Acute myeloid leukemia (AML) is an aggressive disease with a low 5-year overall survival rate of 29.5%. Thus, more effective therapies are in need to prolong survival of AML patients. Mcl-1 is overexpressed in AML and is associated with poor prognosis, representing a promising therapeutic target. The oncoprotein c-Myc is also overexpressed in AML and is a significant prognostic factor. In addition, Mcl-1 is required for c-Myc induced AML, indicating that c-Myc-driven AML harbors a Mcl-1 dependency and co-targeting of Mcl-1 and c-Myc represents a promising strategy to eradicate AML. In this study, we investigated the role of c-Myc in the antileukemic activity of Mcl-1 selective inhibitor AZD5991 and the antileukemic activity of co-targeting of Mcl-1 and c-Myc in preclinical models of AML. We found that c-Myc protein levels negatively correlated with AZD5991 EC50s in AML cell lines and primary patient samples. AZD5991 combined with inhibition of c-Myc synergistically induced apoptosis in AML cell lines and primary patient samples, and cooperatively targeted leukemia progenitor cells. AML cells with acquired resistance to AZD5991 were resensitized to AZD5991 when c-Myc was inhibited. The combination also showed promising and synergistic antileukemic activity in vitro against AML cell lines with acquired resistance to the main chemotherapeutic drug AraC and primary AML cells derived from a patient at relapse post chemotherapy. The oncoprotein c-Myc represents a potential biomarker of AZD5991 sensitivity and inhibition of c-Myc synergistically enhances the antileukemic activity of AZD5991 against AML.
    Keywords:  10058-F4; AZD5991; Acute myeloid leukemia; Mcl-1; c-Myc
    DOI:  https://doi.org/10.1007/s10495-022-01756-7
  6. Haematologica. 2022 Aug 11.
    Potent preclinical activity of FLT3-directed chimeric antigen receptor T cell immunotherapy against FLT3-mutant acute myeloid leukemia and KMT2A-rearranged acute lymphoblastic leukemia.
    Lisa M Niswander, Zachary T Graff, Christopher D Chien, John A Chukinas, Christina A Meadows, Lillie C Leach, Joseph P Loftus, M Eric Kohler, Sarah K Tasian, Terry J Fry.
      Chimeric antigen receptor (CAR) T cell immunotherapies targeting CD19 or CD22 induce remissions in the majority of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), although relapse due to target antigen loss or downregulation has emerged as a major clinical dilemma. Accordingly, great interest exists in developing CAR T cells directed against alternative leukemia cell surface antigens that may help to overcome immunotherapeutic resistance. The fms-like tyrosine kinase 3 receptor (FLT3) is constitutively activated via FLT3 mutation in acute myeloid leukemia (AML) or wild-type FLT3 overexpression in KMT2A (lysine-specific methyltransferase 2A)-rearranged B-acute lymphoblastic leukemia (ALL), which are associated with poor clinical outcomes in children and adults. We developed monovalent FLT3-targeted CAR T cells (FLT3CART) and bispecific CD19xFLT3CART and assessed their anti-leukemia activity in preclinical models of FLT3-mutant AML and KMT2Arearranged infant ALL. We report robust in vitro FLT3CART-induced cytokine production and cytotoxicity against AML and ALL cell lines with minimal cross-reactivity against normal hematopoietic and non-hematopoietic tissues. We also observed potent in vivo inhibition of leukemia proliferation in xenograft models of both FLT3-mutant AML and KMT2A-rearranged ALL, including a post-tisagenlecleucel ALL-to-AML lineage switch patient-derived xenograft model pairing. We further demonstrate significant in vitro and in vivo activity of bispecific CD19xFLT3CART against KMT2A-rearranged ALL and posit that this additional approach might also diminish potential antigen escape in these high-risk leukemias. Our preclinical data credential FLT3CART as a highly effective immunotherapeutic strategy for both FLT3-mutant AML and KMT2A-R ALL that is poised for further investigation and clinical translation.
    DOI:  https://doi.org/10.3324/haematol.2022.281456
  7. Leukemia. 2022 Aug 12.
    Comparison of scoring systems evaluating suitability for intensive chemotherapy in adults with acute myeloid leukemia-a Grand Ouest Against Leukemia (GOAL) study.
    Christophe Desprez, Jérémie Riou, Pierre Peterlin, Tony Marchand, Marie-Anne Couturier, Alban Villate, Jean-Baptiste Mear, Patrice Chevalier, Gaelle Guillerm, Emmanuel Gyan, Aline Schmidt-Tanguy, Roland B Walter, Mathilde Hunault-Berger, Corentin Orvain.
      Several scoring systems have been developed to assess suitability of individual patients for intensive acute myeloid leukemia (AML) therapy. We sought to compare the performance of these scores in a cohort of 428 consecutive adults with AML who received conventional induction chemotherapy in five academic centers in France. All scoring systems identified a subset of patients with increased 28 and 56-day mortality although the prediction accuracy was overall limited with C-statistics of ranging from 0.61 to 0.71 Overall survival (OS) prediction was more limited and restricted to scoring systems that include AML-related parameters. The outcome of 104 patients (24%) considered unsuitable for intensive chemotherapy based on criteria used in recent randomized trials was similar to that of the other 324 patients (28-day mortality, odds ratio [OR] = 1.88, P = 0.2; 56-day mortality, OR = 1.71, P = 0.21; event-free survival, hazard ratio [HR] = 1.08, P = 0.6; OS, HR = 1.25, P = 0.14) with low discrimination (C-statistic: 0.57, 0.56, 0.50, and 0.52 for 28-day, 56-day mortality, EFS, and OS, respectively). Together, our findings indicate that the accuracy of currently available approaches to identify patients at increased risk of early mortality and shortened survival after intensive AML therapy is relatively limited. Caution regarding the use of available scoring systems should be warranted in clinical decision-making.
    DOI:  https://doi.org/10.1038/s41375-022-01677-z
  8. Methods Cell Biol. 2022 ;pii: S0091-679X(22)00049-8. [Epub ahead of print]171 1-22
    Multiple gene knockdown strategies for investigating the properties of human leukemia stem cells and exploring new therapies.
    Andrew Wu, Aysha S Ansari, Hasan Uludaǧ, Xiaoyan Jiang.
      The past two decades have witnessed significant strides in leukemia therapies through approval of therapeutic inhibitors targeting oncogene-driving dysregulated tyrosine kinase activities and key epigenetic and apoptosis regulators. Although these drugs have brought about complete remission in the majority of patients, many patients face relapse or have refractory disease. The main factor contributing to relapse is the presence of a small subpopulation of dormant drug-resistant leukemia cells that possess stem cell features (termed as leukemia stem cells or LSCs). Thus, overcoming drug resistance and targeting LSCs remain major challenges for curative treatment of human leukemia. Chronic myeloid leukemia (CML) is a good example, with rare, propagating LSCs and drug-resistant cells that cannot be eradicated by BCR-ABL-directed tyrosine kinase inhibitor (TKI) monotherapy and that are responsible for disease relapse/progression. Therefore, it is imperative to identify key players in regulating BCR-ABL1-dependent and independent drug-resistance mechanisms, and their key pathways, so that CML LSCs can be selectively targeted or sensitized to TKIs. Here, we describe several easily adaptable gene knockdown approaches in CD34+ CML stem/progenitor cells that can be used to investigate the biological properties of LSCs and molecular effects of genes of interest (GOI), which can be further explored as therapeutic modalities against LSCs in the context of human leukemia.
    Keywords:  AML; CD34(+) stem/progenitor cells; CML; CRISPR-Cas9; FACS; Gene knockdown; LTC-IC; Lentiviral-mediated shRNA; Leukemic stem cells; Lipopolymer/siRNA nanoparticles
    DOI:  https://doi.org/10.1016/bs.mcb.2022.04.002
  9. Ann Hematol. 2022 Aug 08.
    Activation of signaling pathways in models of t(6;9)-acute myeloid leukemia.
    Claudia Chiriches, Dilawar Khan, Maria Wieske, Nathalie Guillen, Michal Rokicki, Carol Guy, Marieangela Wilson, Kate J Heesom, Oliver Gerhard Ottmann, Martin Ruthardt.
      Patients within the WHO-subgroup of t(6;9)-positive acute myeloid leukemia (AML) differ from other AML subgroups as they are characterised by younger age and a grim prognosis. Leukemic transformation can often be attributed to single chromosomal aberrations encoding oncogenes, in the case of t(6;9)-AML to the fusion protein DEK-CAN (also called DEK-NUP214). As being a rare disease there is the urgent need for models of t(6;9)-AML. The only cell line derived from a t(6;9)-AML patient currently available is FKH1. By using phospho-proteomics on FKH1 cells, we found a strongly activated ABL1 kinase. Further investigation revealed the presence of ETV6-ABL1. This finding renders necessary to determine DEK-CAN- and ETV6-ABL1-related features when using FKH1. This can be done as ETV6-ABL1 activity in FKH1 is responsive to imatinib. Nevertheless, we provided evidence that both SFK and mTOR activation in FKH1 are DEK-CAN-related features as they were activated also in other t(6;9) and DEK-CAN-positive models. The activation of STAT5 previously shown to be strong in t(6;9)-AML and activated by DEK-CAN is regulated in FKH1 by both DEK-CAN and ETV6-ABL1. In conclusion, FKH1 cells still represent a model for t(6;9)-AML and could serve as model for ETV6-ABL1-positive AML if the presence of these leukemia-inducing oncogenes is adequately considered.Taken together, all our results provide clear evidence of novel and specific interdependencies between leukemia-inducing oncogenes and cancer signaling pathways which will influence the design of therapeutic strategies to better address the complexity of cancer signaling.
    Keywords:  9); AML; DEK/CAN; ETV6/ABL1; Signaling pathways; Therapy resistance; t(6
    DOI:  https://doi.org/10.1007/s00277-022-04905-9
  10. Leukemia. 2022 Aug 08.
    Alternatively spliced CSF3R isoforms in SRSF2 P95H mutated myeloid neoplasms.
    Borwyn A Wang, Hrishikesh M Mehta, Srinivasa R Penumutchu, Blanton S Tolbert, Chonghui Cheng, Marek Kimmel, Torsten Haferlach, Jaroslaw P Maciejewski, Seth J Corey.
      Alternatively spliced colony stimulating factor 3 receptor (CSF3R) isoforms Class III and Class IV are observed in myelodysplastic syndromes (MDS), but their roles in disease remain unclear. We report that the MDS-associated splicing factor SRSF2 affects the expression of Class III and Class IV isoforms and perturbs granulopoiesis. Add-back of the Class IV isoform in Csf3r-null mouse progenitor cells increased granulocyte progenitors with impaired neutrophil differentiation, while add-back of the Class III produced dysmorphic neutrophils in fewer numbers. These CSF3R isoforms were elevated in patients with myeloid neoplasms harboring SRSF2 mutations. Using in vitro splicing assays, we confirmed increased Class III and Class IV transcripts when SRSF2 P95 mutations were co-expressed with the CSF3R minigene in K562 cells. Since SRSF2 regulates splicing partly by recognizing exonic splicing enhancer (ESE) sequences on pre-mRNA, deletion of either ESE motifs within CSF3R exon 17 decreased Class IV transcript levels without affecting Class III. CD34+ cells expressing SRSF2 P95H showed impaired neutrophil differentiation in response to G-CSF and was accompanied by increased levels of Class IV. Our findings suggest that SRSF2 P95H promotes Class IV splicing by binding to key ESE sequences in CSF3R exon 17, and that SRSF2, when mutated, contributes to dysgranulopoiesis.
    DOI:  https://doi.org/10.1038/s41375-022-01672-4
  11. Leukemia. 2022 Aug 09.
    An immunity and pyroptosis gene-pair signature predicts overall survival in acute myeloid leukemia.
    Weikaixin Kong, Liye He, Jie Zhu, Oscar Brück, Kimmo Porkka, Caroline A Heckman, Sujie Zhu, Tero Aittokallio.
      Treatment responses of patients with acute myeloid leukemia (AML) are known to be heterogeneous, posing challenges for risk scoring and treatment stratification. In this retrospective multi-cohort study, we investigated whether combining pyroptosis- and immune-related genes improves prognostic classification of AML patients. Using a robust gene pairing approach, which effectively eliminates batch effects across heterogeneous patient cohorts and transcriptomic data, we developed an immunity and pyroptosis-related prognostic (IPRP) signature that consists of 15 genes. Using 5 AML cohorts (n = 1327 patients total), we demonstrate that the IPRP score leads to more consistent and accurate survival prediction performance, compared with 10 existing signatures, and that IPRP scoring is widely applicable to various patient cohorts, treatment procedures and transcriptomic technologies. Compared to current standards for AML patient stratification, such as age or ELN2017 risk classification, we demonstrate an added prognostic value of the IPRP risk score for providing improved prediction of AML patients. Our web-tool implementation of the IPRP score and a simple 4-factor nomogram enables practical and robust risk scoring for AML patients. Even though developed for AML patients, our pan-cancer analyses demonstrate a wider application of the IPRP signature for prognostic prediction and analysis of tumor-immune interplay also in multiple solid tumors.
    DOI:  https://doi.org/10.1038/s41375-022-01662-6
  12. Cell Rep. 2022 Aug 09. pii: S2211-1247(22)00990-1. [Epub ahead of print]40(6): 111177
    Phosphoproteomics of primary AML patient samples reveals rationale for AKT combination therapy and p53 context to overcome selinexor resistance.
    Kristina B Emdal, Nicolàs Palacio-Escat, Caroline Wigerup, Akihiro Eguchi, Helén Nilsson, Dorte B Bekker-Jensen, Lars Rönnstrand, Julhash U Kazi, Alexandre Puissant, Raphaël Itzykson, Julio Saez-Rodriguez, Kristina Masson, Peter Blume-Jensen, Jesper V Olsen.
      Acute myeloid leukemia (AML) is a heterogeneous disease with variable patient responses to therapy. Selinexor, an inhibitor of nuclear export, has shown promising clinical activity for AML. To identify the molecular context for monotherapy sensitivity as well as rational drug combinations, we profile selinexor signaling responses using phosphoproteomics in primary AML patient samples and cell lines. Functional phosphosite scoring reveals that p53 function is required for selinexor sensitivity consistent with enhanced efficacy of selinexor in combination with the MDM2 inhibitor nutlin-3a. Moreover, combining selinexor with the AKT inhibitor MK-2206 overcomes dysregulated AKT-FOXO3 signaling in resistant cells, resulting in synergistic anti-proliferative effects. Using high-throughput spatial proteomics to profile subcellular compartments, we measure global proteome and phospho-proteome dynamics, providing direct evidence of nuclear translocation of FOXO3 upon combination treatment. Our data demonstrate the potential of phosphoproteomics and functional phosphorylation site scoring to successfully pinpoint key targetable signaling hubs for rational drug combinations.
    Keywords:  CP: Cancer; CP: Molecular biology; MK-2206; acute myeloid leukemia; combination therapy; drug resistance; functional scoring; mass spectrometry; nutlin-3a; phosphoproteomics; selinexor; subcellular proteomics
    DOI:  https://doi.org/10.1016/j.celrep.2022.111177
  13. Int J Hematol. 2022 Aug 09.
    Sorafenib maintenance after hematopoietic stem cell transplantation improves outcome of FLT3-ITD-mutated acute myeloid leukemia.
    Semra Aydin, Roberto Passera, Matilde Scaldaferri, Chiara Maria Dellacasa, Marco Poggiu, Francesco Cattel, Francesco Zallio, Lucia Brunello, Luisa Giaccone, Irene Dogliotti, Alessandro Busca.
      In a retrospective analysis, 21 acute myeloid leukemia patients receiving single-agent sorafenib maintenance therapy in complete remission (CR) after hematopoietic stem cell transplantation (HSCT) were compared with a control group of 22 patients without maintenance. Sorafenib was initiated a median of 3 months (IQR: 2.3-3.5) after allogeneic HSCT with a median daily dosage of 400 mg (range: 200-800) orally, and lasted a median of 11.3 months (IQR: 3.3-24.4). No significant increase in graft versus host disease or toxicity was observed. Adverse events were reversible with dose adjustment or temporary discontinuation in 19/19 cases. With a median follow-up of 34.7 months (IQR: 16.9-79.5), sorafenib maintenance significantly improved cumulative incidence of relapse (p = 0.028) as well as overall survival (OS) (p = 0.016), especially in patients undergoing allogeneic HSCT in CR1 (p < 0.001). In conclusion, sorafenib maintenance after allogeneic HSCT is safe and may improve cumulative incidence of relapse and OS in FLT3-ITD-mutated AML.
    Keywords:  Acute myeloid leukemia; FLT3–ITD mutation; Hematopoietic stem cell transplantation; Sorafenib maintenance
    DOI:  https://doi.org/10.1007/s12185-022-03427-4
  14. Blood Adv. 2022 Aug 08. pii: bloodadvances.2022008192. [Epub ahead of print]
    Distinguishing STAT3/STAT5B Mutated Large Granular Lymphocyte Leukemia from Myeloid Neoplasms by Genetic Profiling.
    Mark Kavesh, Maedeh Mohebnasab, Marcela Riveros Angel, Wei Xie, Philipp W Raess, Wei Cui, Richard D Press, Guang Yang, Peng Li.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2022008192
  15. Nature. 2022 Aug 10.
    Diverse mutational landscapes in human lymphocytes.
    Heather E Machado, Emily Mitchell, Nina F Øbro, Kirsten Kübler, Megan Davies, Daniel Leongamornlert, Alyssa Cull, Francesco Maura, Mathijs A Sanders, Alex T J Cagan, Craig McDonald, Miriam Belmonte, Mairi S Shepherd, Felipe A Vieira Braga, Robert J Osborne, Krishnaa Mahbubani, Iñigo Martincorena, Elisa Laurenti, Anthony R Green, Gad Getz, Paz Polak, Kourosh Saeb-Parsy, Daniel J Hodson, David G Kent, Peter J Campbell.
      The lymphocyte genome is prone to many threats, including programmed mutation during differentiation1, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.
    DOI:  https://doi.org/10.1038/s41586-022-05072-7
  16. Blood Sci. 2022 Apr;4(2): 65-75
    Single-cell analysis of transcription factor regulatory networks reveals molecular basis for subtype-specific dysregulation in acute myeloid leukemia.
    Ruixia Sun, Lina Sun, Xiaowei Xie, Xuan Li, Peng Wu, Lu Wang, Ping Zhu.
      Highly heterogeneous acute myeloid leukemia (AML) exhibits dysregulated transcriptional programs. Transcription factor (TF) regulatory networks underlying AML subtypes have not been elucidated at single-cell resolution. Here, we comprehensively mapped malignancy-related TFs activated in different AML subtypes by analyzing single-cell RNA sequencing data from AMLs and healthy donors. We first identified six modules of regulatory networks which were prevalently dysregulated in all AML patients. AML subtypes featured with different malignant cellular composition possessed subtype-specific regulatory TFs associated with differentiation suppression or immune modulation. At last, we validated that ERF was crucial for the development of hematopoietic stem/progenitor cells by performing loss- and gain-of-function experiments in zebrafish embryos. Collectively, our work thoroughly documents an abnormal spectrum of transcriptional regulatory networks in AML and reveals subtype-specific dysregulation basis, which provides a prospective view to AML pathogenesis and potential targets for both diagnosis and therapy.
    Keywords:  Acute myeloid leukaemia; Co-expression analysis; Single-cell RNA-sequencing; Transcription factor; Transcriptional regulatory network
    DOI:  https://doi.org/10.1097/BS9.0000000000000113
  17. Blood Cancer Discov. 2022 Aug 12. pii: BCD-22-0011. [Epub ahead of print]
    Pharmacogenomic profiling of pediatric acute myeloid leukemia to identify therapeutic vulnerabilities and inform functional precision medicine.
    Han Wang, Kathy Yuen Yee Chan, Chi Keung Cheng, Margaret H L Ng, Po Yi Lee, Frankie Wai Tsoi Cheng, Grace Kee See Lam, Tin Wai Chow, Shau Yin Ha, Alan K S Chiang, Wing Hang Leung, Anskar Y H Leung, Chi Chiu Wang, Tao Zhang, Xiao-Bing Zhang, Chi Chiu So, Yuet Ping Yuen, Qiwei Sun, Chi Zhang, Yaqun Xu, John Tak Kit Cheung, Wing Hei Ng, Patrick Ming-Kuen Tang, Wei Kang, Ka-Fai To, Wayne Yuk Wai Lee, Raymond Sm Wong, Ellen Ngar Yun Poon, Qi Zhao, Junbin Huang, Chun Chen, Patrick Man Pan Yuen, Chi-Kong Li, Alex Wing Kwan Leung, Kam Tong Leung.
      Despite the expanding portfolio of targeted therapies for adults with acute myeloid leukemia (AML), direct implementation in children is challenging due to inherent differences in underlying genetics. Here we established the pharmacological profile of pediatric AML by screening myeloblast sensitivity to approved and investigational agents, revealing candidates of immediate clinical relevance. Drug responses ex vivo correlated with patient characteristics, exhibited age-specific alterations, and concorded with activities in xenograft models. Integration with genomic data uncovered new gene-drug associations, suggesting actionable therapeutic vulnerabilities. Transcriptome profiling further identified gene expression signatures associated with on- and off-target drug responses. We also demonstrated the feasibility of drug screening-guided treatment for children with high-risk AML, with two evaluable cases achieving remission. Collectively, this study offers a high-dimensional gene-drug-clinical dataset that could be leveraged to research the unique biology of pediatric AML, and sets the stage for realizing functional precision medicine for clinical management of the disease.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-22-0011
  18. Nat Commun. 2022 Aug 08. 13(1): 4611
    Competition between hematopoietic stem and progenitor cells controls hematopoietic stem cell compartment size.
    Runfeng Miao, Harim Chun, Xing Feng, Ana Cordeiro Gomes, Jungmin Choi, João P Pereira.
      Cellular competition for limiting hematopoietic factors is a physiologically regulated but poorly understood process. Here, we studied this phenomenon by hampering hematopoietic progenitor access to Leptin receptor+ mesenchymal stem/progenitor cells (MSPCs) and endothelial cells (ECs). We show that HSC numbers increase by 2-fold when multipotent and lineage-restricted progenitors fail to respond to CXCL12 produced by MSPCs and ECs. HSCs are qualitatively normal, and HSC expansion only occurs when early hematopoietic progenitors but not differentiated hematopoietic cells lack CXCR4. Furthermore, the MSPC and EC transcriptomic heterogeneity is stable, suggesting that it is impervious to major changes in hematopoietic progenitor interactions. Instead, HSC expansion correlates with increased availability of membrane-bound stem cell factor (mSCF) on MSPCs and ECs presumably due to reduced consumption by cKit-expressing hematopoietic progenitors. These studies suggest that an intricate homeostatic balance between HSCs and proximal hematopoietic progenitors is regulated by cell competition for limited amounts of mSCF.
    DOI:  https://doi.org/10.1038/s41467-022-32228-w
  19. Future Oncol. 2022 Aug 11.
    Phase III MANIFEST-2: pelabresib + ruxolitinib vs placebo + ruxolitinib in JAK inhibitor treatment-naive myelofibrosis.
    Claire N Harrison, Vikas K Gupta, Aaron T Gerds, Raajit Rampal, Srdan Verstovsek, Moshe Talpaz, Jean-Jacques Kiladjian, Ruben Mesa, Andrew T Kuykendall, Alessandro M Vannucchi, Francesca Palandri, Sebastian Grosicki, Timothy Devos, Eric Jourdan, Marielle J Wondergem, Haifa Kathrin Al-Ali, Veronika Buxhofer-Ausch, Alberto Alvarez-Larrán, Andrea Patriarca, Marina Kremyanskaya, Adam J Mead, Sanjay Akhani, Yuri Sheikine, Gozde Colak, John Mascarenhas.
      Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).
    Keywords:  CPI-0610; JAKi treatment-naive; MANIFEST-2; myelofibrosis; pelabresib; ruxolitinib
    DOI:  https://doi.org/10.2217/fon-2022-0484
  20. Nat Commun. 2022 Aug 09. 13(1): 4674
    MYC sensitises cells to apoptosis by driving energetic demand.
    Joy Edwards-Hicks, Huizhong Su, Maurizio Mangolini, Kubra K Yoneten, Jimi Wills, Giovanny Rodriguez-Blanco, Christine Young, Kevin Cho, Heather Barker, Morwenna Muir, Ania Naila Guerrieri, Xue-Feng Li, Rachel White, Piotr Manasterski, Elena Mandrou, Karen Wills, Jingyu Chen, Emily Abraham, Kianoosh Sateri, Bin-Zhi Qian, Peter Bankhead, Mark Arends, Noor Gammoh, Alex von Kriegsheim, Gary J Patti, Andrew H Sims, Juan Carlos Acosta, Valerie Brunton, Kamil R Kranc, Maria Christophorou, Erika L Pearce, Ingo Ringshausen, Andrew J Finch.
      The MYC oncogene is a potent driver of growth and proliferation but also sensitises cells to apoptosis, which limits its oncogenic potential. MYC induces several biosynthetic programmes and primary cells overexpressing MYC are highly sensitive to glutamine withdrawal suggesting that MYC-induced sensitisation to apoptosis may be due to imbalance of metabolic/energetic supply and demand. Here we show that MYC elevates global transcription and translation, even in the absence of glutamine, revealing metabolic demand without corresponding supply. Glutamine withdrawal from MRC-5 fibroblasts depletes key tricarboxylic acid (TCA) cycle metabolites and, in combination with MYC activation, leads to AMP accumulation and nucleotide catabolism indicative of energetic stress. Further analyses reveal that glutamine supports viability through TCA cycle energetics rather than asparagine biosynthesis and that TCA cycle inhibition confers tumour suppression on MYC-driven lymphoma in vivo. In summary, glutamine supports the viability of MYC-overexpressing cells through an energetic rather than a biosynthetic mechanism.
    DOI:  https://doi.org/10.1038/s41467-022-32368-z
  21. Leuk Res Rep. 2022 ;18 100340
    Gilteritinib as treatment for extra-medullary relapse of FLT3-ITD acute myeloid leukemia FLT3-ITD, after allogeneic haematopoietic stem cell transplantation.
    R Iannotta, M Celentano, S Marotta, C M Pedata, C Riccardi, I Migliaccio, A Viola, S M Muggianu, C Falco, D Bovenzi, F Ferrara, A Picardi.
      Case of a patient with acute myeloid leukemia (AML) positive for mutations in both genes NPM1 and FLT3-ITD who underwent two allogeneic haematopoietic stem cell transplants (HSCT); the second allograft one was followed by extramedullary relapse (granulocytic sarcoma of right breast), with blast cells positive for FLT3-ITDmutation.  Treatment with Gilteritinib, a second generation selective oral type I FLT3 inhibitor, was started after the second HSCT with complete regression of breast granulocytic sarcoma in absence of hematological and extra hematologic toxicity. We conclude that Gilteritinib can represent an effective therapy for extra hematologic relapse, with acceptable toxicity and outpatient management.
    Keywords:  Acute myeloid leukemia FLT3 ITD positive; Extramedullary relapse FLT3 ITD positive; Gilteritinib; HSCT allogeneic haematopoietic stem cell transplants
    DOI:  https://doi.org/10.1016/j.lrr.2022.100340
  22. Hemasphere. 2022 Aug;6(8): e757
    A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.
    Claire Harrison, Florian H Heidel, Alessandro M Vannucchi, Jean-Jacques Kiladjian, Amjad Hayat, Francesco Passamonti, Eibhlin Conneally, Thomas Kindler, Bruno Martino, Daniel B Lipka, Tommaso Stefanelli, Pantelia Roussou, Davide Germano, Jacqueline Ewan, Vincent Ribrag.
      
    DOI:  https://doi.org/10.1097/HS9.0000000000000757
  23. Exp Hematol. 2022 Aug 05. pii: S0301-472X(22)00582-3. [Epub ahead of print]
    The Impact of Clonal Hematopoiesis on Cardiovascular Disease in People Living with HIV.
    Brian Wiley, Tyler M Parsons, Samantha Burkart, Andrew L Young, Kristine M Erlandson, Katherine K Tassiopoulos, Kunling Wu, Christina Gurnett, Rachel M Presti, Kelly L Bolton, Grant A Challen.
      Hematopoietic stem cells (HSCs) with age-associated somatic mutations that disproportionally contribute to hematopoiesis generate the condition known as clonal hematopoiesis (CH). While CH conveys increased risk of hematologic cancer, there is also strong association between CH and cardiovascular disease (CVD). Accumulating evidence suggests that inflammation mechanistically links CH to CVD, and we hypothesized that CH may be a predictive biomarker of CVD in conditions of chronic inflammation. One such patient population is people living with HIV (PLWH) who also have substantially increased incidence of CVD and CH [1]. We studied the association between CH and CVD in PLWH using samples from ACTG Study A5001 (or ALLRT), a prospective clinical trial of HIV-infected persons with long term follow-up. We observed a positive association between CH and CVD in PLWH independent of traditional CVD risk factors. Moreover, in CVD cases the CH clone was identifiable in the blood years prior to CVD diagnosis, unlike PLWH with CH who did not suffer CVD. With the lifespan of PLWH increasing due to advances in treatment, our results indicate that the presence of CH and its clonal dynamics could be used as a prognostic biomarker to risk of CVD in PLWH.
    DOI:  https://doi.org/10.1016/j.exphem.2022.07.304
  24. Blood. 2022 Aug 12. pii: blood.2022016567. [Epub ahead of print]
    Pre-transplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines post-transplant clinical outcome.
    Sun Loo, Richard Dillon, Adam Ivey, Natasha S Anstee, Jad Othman, Ing Soo Tiong, Nicola Potter, Jelena Jovanovic, Manohursingh Runglall, Chong Chyn Chua, Ashish Bajel, David S Ritchie, Kelli Gray, Zhi Han Yeoh, Michelle McBean, Amanda Frances Gilkes, Ian Thomas, Sean Johnson, Nigel H Russell, Andrew H Wei.
      
    DOI:  https://doi.org/10.1182/blood.2022016567
  25. Nat Commun. 2022 Aug 11. 13(1): 4724
    Ultra-deep sequencing validates safety of CRISPR/Cas9 genome editing in human hematopoietic stem and progenitor cells.
    M Kyle Cromer, Valentin V Barsan, Erich Jaeger, Mengchi Wang, Jessica P Hampton, Feng Chen, Drew Kennedy, Jenny Xiao, Irina Khrebtukova, Ana Granat, Tiffany Truong, Matthew H Porteus.
      As CRISPR-based therapies enter the clinic, evaluation of safety remains a critical and active area of study. Here, we employ a clinical next generation sequencing (NGS) workflow to achieve high sequencing depth and detect ultra-low frequency variants across exons of genes associated with cancer, all exons, and genome wide. In three separate primary human hematopoietic stem and progenitor cell (HSPC) donors assessed in technical triplicates, we electroporated high-fidelity Cas9 protein targeted to three loci (AAVS1, HBB, and ZFPM2) and harvested genomic DNA at days 4 and 10. Our results demonstrate that clinically relevant delivery of high-fidelity Cas9 to primary HSPCs and ex vivo culture up to 10 days does not introduce or enrich for tumorigenic variants and that even a single SNP in a gRNA spacer sequence is sufficient to eliminate Cas9 off-target activity in primary, repair-competent human HSPCs.
    DOI:  https://doi.org/10.1038/s41467-022-32233-z
  26. Front Oncol. 2022 ;12 876981
    A distinct lipid metabolism signature of acute myeloid leukemia with prognostic value.
    Ding Li, Jiaming Liang, Wei Yang, Wenbin Guo, Wenping Song, Wenzhou Zhang, Xuan Wu, Baoxia He.
       Background: Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy characterized by extensive genetic abnormalities that might affect the prognosis and provide potential drug targets for treatment. Reprogramming of lipid metabolism plays important roles in tumorigenesis and progression and has been newly recognized a new hallmark of malignancy, and some related molecules in the signal pathways could be prognostic biomarkers and potential therapeutic targets for cancer treatment. However, the clinical value of lipid metabolism reprogramming in AML has not been systematically explored. In this study, we aim to explore the clinical value of lipid metabolism reprogramming and develop a prognostic risk signature for AML.
    Methods: We implemented univariate Cox regression analysis to identify the prognosis-related lipid metabolism genes, and then performed LASSO analysis to develop the risk signature with six lipid metabolism-related genes (LDLRAP1, PNPLA6, DGKA, PLA2G4A, CBR1, and EBP). The risk scores of samples were calculated and divided into low- and high-risk groups by the median risk score.
    Results: Survival analysis showed the high-risk group hold the significantly poorer outcomes than the low-risk group. The signature was validated in the GEO datasets and displayed a robust prognostic value in the stratification analysis. Multivariate analysis revealed the signature was an independent prognostic factor for AML patients and could serve as a potential prognostic biomarker in clinical evaluation. Furthermore, the risk signature was also found to be closely related to immune landscape and immunotherapy response in AML.
    Conclusions: Overall, we conducted a comprehensive analysis of lipid metabolism in AML and constructed a risk signature with six genes related to lipid metabolism for the malignancy, prognosis, and immune landscape of AML, and our study might contribute to better understanding in the use of metabolites and metabolic pathways as the potential prognostic biomarkers and therapeutic targets for AML.
    Keywords:  acute myeloid leukemia; immune landscape; lipid metabolism; prognosis; risk signature
    DOI:  https://doi.org/10.3389/fonc.2022.876981
  27. Front Cell Dev Biol. 2022 ;10 930205
    The Anti-Leukemia Effect of Ascorbic Acid: From the Pro-Oxidant Potential to the Epigenetic Role in Acute Myeloid Leukemia.
    S Travaglini, C Gurnari, S Antonelli, G Silvestrini, N I Noguera, T Ottone, M T Voso.
      Data derived from high-throughput sequencing technologies have allowed a deeper understanding of the molecular landscape of Acute Myeloid Leukemia (AML), paving the way for the development of novel therapeutic options, with a higher efficacy and a lower toxicity than conventional chemotherapy. In the antileukemia drug development scenario, ascorbic acid, a natural compound also known as Vitamin C, has emerged for its potential anti-proliferative and pro-apoptotic activities on leukemic cells. However, the role of ascorbic acid (vitamin C) in the treatment of AML has been debated for decades. Mechanistic insight into its role in many biological processes and, especially, in epigenetic regulation has provided the rationale for the use of this agent as a novel anti-leukemia therapy in AML. Acting as a co-factor for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), ascorbic acid is involved in the epigenetic regulations through the control of TET (ten-eleven translocation) enzymes, epigenetic master regulators with a critical role in aberrant hematopoiesis and leukemogenesis. In line with this discovery, great interest has been emerging for the clinical testing of this drug targeting leukemia epigenome. Besides its role in epigenetics, ascorbic acid is also a pivotal regulator of many physiological processes in human, particularly in the antioxidant cellular response, being able to scavenge reactive oxygen species (ROS) to prevent DNA damage and other effects involved in cancer transformation. Thus, for this wide spectrum of biological activities, ascorbic acid possesses some pharmacologic properties attractive for anti-leukemia therapy. The present review outlines the evidence and mechanism of ascorbic acid in leukemogenesis and its therapeutic potential in AML. With the growing evidence derived from the literature on situations in which the use of ascorbate may be beneficial in vitro and in vivo, we will finally discuss how these insights could be included into the rational design of future clinical trials.
    Keywords:  acute myeloid leukemia; ascorbic acid; epigenetic regulation; oxidative stress; vitamin C
    DOI:  https://doi.org/10.3389/fcell.2022.930205
  28. Blood Rev. 2022 Jul 19. pii: S0268-960X(22)00065-0. [Epub ahead of print] 100991
    Blasts in context: the impact of the immune environment on acute myeloid leukemia prognosis and treatment.
    Yasmina Serroukh, Josée Hébert, Lambert Busque, François Mercier, Christopher E Rudd, Sarit Assouline, Silvy Lachance, Jean-Sébastien Delisle.
      Acute myeloid leukemia (AML) is a cancer that originates from the bone marrow (BM). Under physiological conditions, the bone marrow supports the homeostasis of immune cells and hosts memory lymphoid cells. In this review, we summarize our present understanding of the role of the immune microenvironment on healthy bone marrow and on the development of AML, with a focus on T cells and other lymphoid cells. The types and function of different immune cells involved in the AML microenvironment as well as their putative role in the onset of disease and response to treatment are presented. We also describe how the immune context predicts the response to immunotherapy in AML and how these therapies modulate the immune status of the bone marrow. Finally, we focus on allogeneic stem cell transplantation and summarize the current understanding of the immune environment in the post-transplant bone marrow, the factors associated with immune escape and relevant strategies to prevent and treat relapse.
    Keywords:  Acute myeloid leukemia; Bone marrow; Cellular therapy; Hematopoietic stem cell transplantation; Immune environment; Immunotherapy
    DOI:  https://doi.org/10.1016/j.blre.2022.100991
  29. Cell Chem Biol. 2022 Aug 09. pii: S2451-9456(22)00275-6. [Epub ahead of print]
    Discovery of compounds that reactivate p53 mutants in vitro and in vivo.
    Geetha Durairaj, Özlem Demir, Bryant Lim, Roberta Baronio, Delia Tifrea, Linda V Hall, Jacob C DeForest, Linda Lauinger, Maryam M Jebril Fallatah, Clinton Yu, Hosung Bae, Da-Wei Lin, Jin Kwang Kim, Faezeh Salehi, Cholsoon Jang, Feng Qiao, Richard H Lathrop, Lan Huang, Robert Edwards, Scott Rychnovsky, Rommie E Amaro, Peter Kaiser.
      The tumor suppressor p53 is the most frequently mutated protein in human cancer. The majority of these mutations are missense mutations in the DNA binding domain of p53. Restoring p53 tumor suppressor function could have a major impact on the therapy for a wide range of cancers. Here we report a virtual screening approach that identified several small molecules with p53 reactivation activities. The UCI-LC0023 compound series was studied in detail and was shown to bind p53, induce a conformational change in mutant p53, restore the ability of p53 hotspot mutants to associate with chromatin, reestablish sequence-specific DNA binding of a p53 mutant in a reconstituted in vitro system, induce p53-dependent transcription programs, and prevent progression of tumors carrying mutant p53, but not p53null or p53WT alleles. Our study demonstrates feasibility of a computation-guided approach to identify small molecule corrector drugs for p53 hotspot mutations.
    Keywords:  cryptic pocket; ensemble based virtual screening; molecular dynamics simulations; mutant p53; p53 reactivation; small molecule p53 corrector drugs
    DOI:  https://doi.org/10.1016/j.chembiol.2022.07.003
  30. Leukemia. 2022 Aug 06.
    Minimal residual disease in BCR::ABL1-positive acute lymphoblastic leukemia: different significance in typical ALL and in CML-like disease.
    Jan Zuna, Lenka Hovorkova, Justina Krotka, Amelie Koehrmann, Michela Bardini, Lucie Winkowska, Eva Fronkova, Julia Alten, Rolf Koehler, Cornelia Eckert, Lisa Brizzolara, Marie Trkova, Jan Stuchly, Martin Zimmermann, Paola De Lorenzo, Maria Grazia Valsecchi, Valentino Conter, Jan Stary, Martin Schrappe, Andrea Biondi, Jan Trka, Marketa Zaliova, Giovanni Cazzaniga, Gunnar Cario.
      Recently, we defined "CML-like" subtype of BCR::ABL1-positive acute lymphoblastic leukemia (ALL), resembling lymphoid blast crisis of chronic myeloid leukemia (CML). Here we retrospectively analyzed prognostic relevance of minimal residual disease (MRD) and other features in 147 children with BCR::ABL1-positive ALL (diagnosed I/2000-IV/2021, treated according to EsPhALL (n = 133) or other (n = 14) protocols), using DNA-based monitoring of BCR::ABL1 genomic breakpoint and clonal immunoglobulin/T-cell receptor gene rearrangements. Although overall prognosis of CML-like (n = 48) and typical ALL (n = 99) was similar (5-year-EFS 60% and 49%, respectively; 5-year-OS 75% and 73%, respectively), typical ALL presented more relapses while CML-like patients more often died in the first remission. Prognostic role of MRD was significant in the typical ALL (p = 0.0005 in multivariate analysis for EFS). In contrast, in CML-like patients MRD was not significant (p values > 0.2) and inapplicable for therapy adjustment. Moreover, in the typical ALL, risk-prediction could be further improved by considering initial hyperleukocytosis. Early distinguishing typical BCR::ABL1-positive ALL and CML-like patients is essential to enable optimal treatment approach in upcoming protocols. For the typical ALL, tyrosine-kinase inhibitors and concurrent chemotherapy with risk-directed intensity should be recommended; in the CML-like disease, no relevant prognostic feature applicable for therapy tailoring was found so far.
    DOI:  https://doi.org/10.1038/s41375-022-01668-0
  31. Nature. 2022 Aug 10.
    Truncated FGFR2 is a clinically actionable oncogene in multiple cancers.
    Daniel Zingg, Jinhyuk Bhin, Julia Yemelyanenko, Sjors M Kas, Frank Rolfs, Catrin Lutz, Jessica K Lee, Sjoerd Klarenbeek, Ian M Silverman, Stefano Annunziato, Chang S Chan, Sander R Piersma, Timo Eijkman, Madelon Badoux, Ewa Gogola, Bjørn Siteur, Justin Sprengers, Bim de Klein, Richard R de Goeij-de Haas, Gregory M Riedlinger, Hua Ke, Russell Madison, Anne Paulien Drenth, Eline van der Burg, Eva Schut, Linda Henneman, Martine H van Miltenburg, Natalie Proost, Huiling Zhen, Ellen Wientjens, Roebi de Bruijn, Julian R de Ruiter, Ute Boon, Renske de Korte-Grimmerink, Bastiaan van Gerwen, Luis Féliz, Ghassan K Abou-Alfa, Jeffrey S Ross, Marieke van de Ven, Sven Rottenberg, Edwin Cuppen, Anne Vaslin Chessex, Siraj M Ali, Timothy C Burn, Connie R Jimenez, Shridar Ganesan, Lodewyk F A Wessels, Jos Jonkers.
      Somatic hotspot mutations and structural amplifications and fusions that affect fibroblast growth factor receptor 2 (encoded by FGFR2) occur in multiple types of cancer1. However, clinical responses to FGFR inhibitors have remained variable1-9, emphasizing the need to better understand which FGFR2 alterations are oncogenic and therapeutically targetable. Here we apply transposon-based screening10,11 and tumour modelling in mice12,13, and find that the truncation of exon 18 (E18) of Fgfr2 is a potent driver mutation. Human oncogenomic datasets revealed a diverse set of FGFR2 alterations, including rearrangements, E1-E17 partial amplifications, and E18 nonsense and frameshift mutations, each causing the transcription of E18-truncated FGFR2 (FGFR2ΔE18). Functional in vitro and in vivo examination of a compendium of FGFR2ΔE18 and full-length variants pinpointed FGFR2-E18 truncation as single-driver alteration in cancer. By contrast, the oncogenic competence of FGFR2 full-length amplifications depended on a distinct landscape of cooperating driver genes. This suggests that genomic alterations that generate stable FGFR2ΔE18 variants are actionable therapeutic targets, which we confirmed in preclinical mouse and human tumour models, and in a clinical trial. We propose that cancers containing any FGFR2 variant with a truncated E18 should be considered for FGFR-targeted therapies.
    DOI:  https://doi.org/10.1038/s41586-022-05066-5
  32. Genome Biol. 2022 Aug 09. 23(1): 173
    Single-cell diploid Hi-C reveals the role of spatial aggregations in complex rearrangements and KMT2A fusions in leukemia.
    Zhihao Xing, Huirong Mai, Xiaorong Liu, Xiaoying Fu, Xingliang Zhang, Lichun Xie, Yunsheng Chen, Adam Shlien, Feiqiu Wen.
       BACKGROUND: Simple translocations and complex rearrangements are formed through illegitimate ligations of double-strand breaks of fusion partners and lead to generation of oncogenic fusion genes that affect cellular function. The contact first hypothesis states that fusion partners tend to colocalize prior to fusion in normal cells. Here we test this hypothesis at the single-cell level and explore the underlying mechanism.
    RESULTS: By analyzing published single-cell diploid Hi-C datasets, we find partner genes fused in leukemia exhibit smaller spatial distances than those fused in solid tumor and control gene pairs. Intriguingly, multiple partners tend to colocalize with KMT2A in the same cell. 3D genome architecture has little association with lineage decision of KMT2A fusion types in leukemia. Besides simple translocations, complex rearrangement-related KMT2A fusion genes (CRGs) also show closer proximity and belong to a genome-wide mutual proximity network. We find CRGs are co-expressed, co-localized, and enriched in the targets of the transcriptional factor RUNX1, suggesting they may be involved in RUNX1-mediated transcription factories. Knockdown of RUNX1 leads to significantly fewer contacts among CRGs. We also find CRGs are enriched in active transcriptional regions and loop anchors, and exhibit high levels of TOP2-mediated DNA breakages. Inhibition of transcription leads to reduced DNA breakages of CRGs.
    CONCLUSIONS: Our results demonstrate KMT2A partners and CRGs may form dynamic and multipartite spatial clusters in individual cells that may be involved in RUNX1-mediated transcription factories, wherein massive DNA damages and illegitimate ligations of genes may occur, leading to complex rearrangements and KMT2A fusions in leukemia.
    Keywords:  Complex rearrangements; Fusions; Genomic rearrangements; Leukemia; Single-cell Hi-C
    DOI:  https://doi.org/10.1186/s13059-022-02740-9
  33. Haematologica. 2022 Aug 11.
    Osteoprogenitor SFRP1 prevents exhaustion of hematopoietic stem cells via PP2A-PR72/130-mediated regulation of p300.
    Franziska Hettler, Christina Schreck, Sandra Romero Marquez, Thomas Engleitner, Baiba Vilne, Theresa Landspersky, Heike Weidner, Renate Hausinger, Ritu Mishra, Rupert Oellinger, Martina Rauner, Ronald Naumann, Christian Peschel, Florian Bassermann, Roland Rad, Rouzanna Istvanffy, Robert A J Oostendorp.
      Remodeling of the bone marrow microenvironment in chronic inflammation and in aging reduces hematopoietic stem cell (HSC) function. To assess the mechanisms of HSC functional decline and find strategies to counteract these, we established a model in which Sfrp1 gene was deleted in Osterix+ osteolineage cells (OS1Δ/Δ mice). HSCs from these mice showed severely diminished repopulating activity with associated DNA damage, enriched expression of the `ROS pathway´ and reduced single cell proliferation. Interestingly, not only was the protein level of Catenin beta-1 (beta-catenin) elevated, but so was its association with the phosphorylated coactivator p300 in the nucleus. Since these two proteins play a key role in promotion of differentiation and senescence, we inhibited in vivo phosphorylation of p300 through PP2APR72/130 by IQ-1 administration in OS1Δ/Δ mice. This treatment not only reduced Catenin beta-1/phospho-p300 association, but also decreased nuclear p300. More importantly, in vivo IQ-1 treatment fully restored HSC repopulating activity of the OS1Δ/Δ mice. Our findings show that osteoprogenitor Sfrp1 is essential for maintaining HSC function. Furthermore, pharmacological downregulation of nuclear Catenin beta-1/phospho-p300 association is a new strategy to restore poor HSC function.
    DOI:  https://doi.org/10.3324/haematol.2022.280760
  34. Science. 2022 Apr 22. pii: science.abl9283. [Epub ahead of print]376(6591):
    Substitution mutational signatures in whole-genome-sequenced cancers in the UK population.
    Genomics England Research Consortium
      Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.
    DOI:  https://doi.org/10.1126/science.abl9283
  35. Nat Commun. 2022 Aug 12. 13(1): 4739
    Generation of a CRISPR activation mouse that enables modelling of aggressive lymphoma and interrogation of venetoclax resistance.
    Yexuan Deng, Sarah T Diepstraten, Margaret A Potts, Göknur Giner, Stephanie Trezise, Ashley P Ng, Gerry Healey, Serena R Kane, Amali Cooray, Kira Behrens, Amy Heidersbach, Andrew J Kueh, Martin Pal, Stephen Wilcox, Lin Tai, Warren S Alexander, Jane E Visvader, Stephen L Nutt, Andreas Strasser, Benjamin Haley, Quan Zhao, Gemma L Kelly, Marco J Herold.
      CRISPR technologies have advanced cancer modelling in mice, but CRISPR activation (CRISPRa) methods have not been exploited in this context. We establish a CRISPRa mouse (dCas9a-SAMKI) for inducing gene expression in vivo and in vitro. Using dCas9a-SAMKI primary lymphocytes, we induce B cell restricted genes in T cells and vice versa, demonstrating the power of this system. There are limited models of aggressive double hit lymphoma. Therefore, we transactivate pro-survival BCL-2 in Eµ-MycT/+;dCas9a-SAMKI/+ haematopoietic stem and progenitor cells. Mice transplanted with these cells rapidly develop lymphomas expressing high BCL-2 and MYC. Unlike standard Eµ-Myc lymphomas, BCL-2 expressing lymphomas are highly sensitive to the BCL-2 inhibitor venetoclax. We perform genome-wide activation screens in these lymphoma cells and find a dominant role for the BCL-2 protein A1 in venetoclax resistance. Here we show the potential of our CRISPRa model for mimicking disease and providing insights into resistance mechanisms towards targeted therapies.
    DOI:  https://doi.org/10.1038/s41467-022-32485-9
  36. Nat Genet. 2022 Aug 11.
    Substantial somatic genomic variation and selection for BCOR mutations in human induced pluripotent stem cells.
    Foad J Rouhani, Xueqing Zou, Petr Danecek, Cherif Badja, Tauanne Dias Amarante, Gene Koh, Qianxin Wu, Yasin Memari, Richard Durbin, Inigo Martincorena, Andrew R Bassett, Daniel Gaffney, Serena Nik-Zainal.
      We explored human induced pluripotent stem cells (hiPSCs) derived from different tissues to gain insights into genomic integrity at single-nucleotide resolution. We used genome sequencing data from two large hiPSC repositories involving 696 hiPSCs and daughter subclones. We find ultraviolet light (UV)-related damage in ~72% of skin fibroblast-derived hiPSCs (F-hiPSCs), occasionally resulting in substantial mutagenesis (up to 15 mutations per megabase). We demonstrate remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming due to oligoclonal fibroblast populations. In contrast, blood-derived hiPSCs (B-hiPSCs) had fewer mutations and no UV damage but a high prevalence of acquired BCOR mutations (26.9% of lines). We reveal strong selection pressure for BCOR mutations in F-hiPSCs and B-hiPSCs and provide evidence that they arise in vitro. Directed differentiation of hiPSCs and RNA sequencing showed that BCOR mutations have functional consequences. Our work strongly suggests that detailed nucleotide-resolution characterization is essential before using hiPSCs.
    DOI:  https://doi.org/10.1038/s41588-022-01147-3
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